Gerlies Treiber

Vitamin D and immune function.

Vitamin D metabolizing enzymes and vitamin D receptors are present in many cell types including various immune cells such as antigen-presenting-cells, T cells, B cells and monocytes. In vitro data show that, in addition to modulating innate immune cells, vitamin D also promotes a more tolerogenic immunological status. In vivo data from animals and from human vitamin D supplementation studies have shown beneficial effects of vitamin D on immune function, in particular in the context of autoimmunity. In this review, currently available data are summarized to give an overview of the effects of vitamin D on the immune system in general and on the regulation of inflammatory responses, as well as regulatory mechanisms connected to autoimmune diseases particularly in type 1 diabetes mellitus.

Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial.

Vitamin D deficiency is a risk factor for arterial hypertension, but randomized controlled trials showed mixed effects of vitamin D supplementation on blood pressure (BP). We aimed to evaluate whether vitamin D supplementation affects 24-hour systolic ambulatory BP monitoring values and cardiovascular risk factors. The Styrian Vitamin D Hypertension Trial is a single-center, double-blind, placebo-controlled study conducted from June 2011 to August 2014 at the endocrine outpatient clinic of the Medical University of Graz, Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxyvitamin D levels below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day as oily drops (n=100) or placebo (n=100) for 8 weeks. Primary outcome measure was 24-hour systolic BP. Secondary outcome measures were 24-hour diastolic BP, N-terminal-pro-B-type natriuretic peptide, QTc interval, renin, aldosterone, 24-hour urinary albumin excretion, homeostasis model assessment-insulin resistance, triglycerides, high-density lipoprotein cholesterol, and pulse wave velocity. A total of 188 participants (mean [SD] age, 60.1 [11.3] years; 47% women; 25-hydroxyvitamin D, 21.2 [5.6] ng/mL) completed the trial. The mean treatment effect (95% confidence interval) for 24-hour systolic BP was −0.4 (−2.8 to 1.9) mm Hg (P=0.712). Triglycerides increased significantly (mean change [95% confidence interval], 17 [1–33] mg/dL; P=0.013), but no further significant effects were observed for secondary outcomes. Vitamin D supplementation in hypertensive patients with low 25-hydroxyvitamin D has no significant effect on BP and several cardiovascular risk factors, but it was associated with a significant increase in triglycerides. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02136771.

Evaluation of subcutaneous glucose monitoring systems under routine environmental conditions in patients with type 1 diabetes

Continuous and flash glucose monitoring (GM) systems have been established in diabetes care. We compared the sensor performance of 3 commercially available GM systems. A total of 12 patients with type 1 diabetes were included in a single‐centre, open‐label study in which the sensor performance of the Abbott FreeStyle libre (Abbott), Dexcom G4 Platinum (Dexcom) and Medtronic MiniMed 640G (Medtronic) systems over 12 hours was compared during mimicked real‐life conditions (meals, exercise, hypo‐ and hyperglycaemia). Sensor performance was determined by fulfilment of ISO 15197:2013 criteria, calculating mean absolute relative difference (MARD), and was also illustrated using Parkes error grid and Bland–Altman plots. Sensor performance during changes in metabolic variables (lactate, betahydroxybutyrate, glucagon, non‐esterified‐fatty‐acids) was determined by Spearmans rank correlation coefficient testing. The systems fulfilled ISO 15197:2013 criteria by 73.2% (Abbott), 56.1% (Dexcom) and 52.0% (Medtronic). The MARDs ± standard deviation in the entire glycaemic range were 13.2% ± 10.9% (Abbott), 16.8% ± 12.3% (Dexcom) and 21.4% ± 17.6% (Medtronic), respectively. All sensors performed less accurately during hypoglycaemia and best during hyperglycaemia. We did not observe an influence of metabolic variables on sensor performance.

Pharmacodynamics of the long‐acting insulin analogues detemir and glargine following single‐doses and under steady‐state conditions in patients with type 1 diabetes

The pharmacodynamic characteristics of the basal insulin analogues insulin detemir (IDet) and insulin glargine (IGlar) have been examined extensively via euglycaemic clamp studies. However, differences in clamp methodology and in the analysis of clamp data between trials have led to confusion over the duration of action of these two insulins. The aim of this study was to address these ambiguities in the literature by assessing the pharmacodynamic properties of IDet and IGlar over 30 h under single‐dose and steady‐state conditions using the definitions and procedures previously standardized by Heise and Pieber in 2007.

Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus - A randomized clinical trial.

It is unknown if cholecalciferol is able to modify defects in regulatory T cells (Tregs) in type 1 diabetes (T1D). In this randomized, double-blind, placebo controlled trial 30 young patients with new-onset T1D were assigned to cholecalciferol (70IU/kgbodyweight/day) or placebo for 12months. Tregs were determined by FACS-analysis and functional tests were assessed with ex vivo suppression co-cultures at months 0, 3, 6 and 12. Suppressive capacity of Tregs increased (p<0.001) with cholecalciferol from baseline (-1.59±25.6%) to 3 (30.5±39.4%), 6 (44.6±23.8%) and 12months (37.2±25.0%) and change of suppression capacity from baseline to 12months was significantly higher (p<0.05) with cholecalciferol (22.2±47.2%) than placebo (-16.6±21.1%). Serum calcium and parathormone stayed within normal range. This is the first study, which showed that cholecalciferol improved suppressor function of Tregs in patients with T1D and vitamin D could serve as one possible agent in the development of immunomodulatory combination therapies for T1D.

Ultra-Long Pharmacokinetic Properties of Insulin Degludec are Comparable in Elderly Subjects and Younger Adults with Type 1 Diabetes Mellitus

AbstractBackgroundManagement of diabetes in elderly subjects is complex and careful management of glucose levels is of particular importance in this population because of an increased risk of diabetes-related complications and hypoglycaemia.ObjectiveThe aim of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a basal insulin with an ultra-long duration of action, in elderly subjects with type 1 diabetes compared with younger adults.MethodsThis trial was a randomised, double-blind, two-period, crossover trial conducted in a single centre and included both inpatient and outpatient periods. Subjects were men and women aged 18–35 years inclusive (younger adult group) or ≥65 years (elderly group) with type 1 diabetes who received IDeg (0.4 U/kg) via subcutaneous injection in the thigh once-daily for six days. Following 6-day dosing, a 26-hour euglycaemic glucose clamp procedure was conducted to evaluate the steady-state pharmacodynamic effects of IDeg. Blood samples were taken for pharmacokinetic analysis up to 120 h post-dose. Pharmacokinetic endpoints included the total exposure of IDeg, ie the area under the IDeg serum concentration curve during one dosing interval at steady state (AUCIDeg,τ,SS) (τ = 0–24 h, equal to one dosing interval) and the maximum IDeg serum concentration at steady state (Cmax,IDeg,SS). Pharmacodynamic endpoints included the total glucose-lowering effect of IDeg, ie the area under the glucose infusion rate (GIR) curve at steady state (AUCGIR,τ,SS), and the maximum GIR at steady state (GIRmax,IDeg,SS).ResultsTotal exposure (AUCIDeg,τ,SS) and maximum concentration (Cmax,IDeg,SS) of IDeg were comparable between elderly subjects and younger adults. Estimated mean age group ratios (elderly/younger adult) for AUCIDeg,τ,SS and Cmax,IDeg,SS and corresponding two-sided 95 % confidence intervals (CIs) were 1.04 (95 % CI 0.73–1.47) and 1.02 (95 % CI 0.74–1.39), respectively. Mean AUCIDeg,0–12h,SS/AUCIDeg,τ,SS was 53 % in both younger adult and elderly subjects, showing that in both age groups IDeg exposure was evenly distributed across the first and second 12 h of the 24-hour dosing interval. No statistically significant differences were observed between younger adult and elderly subjects with regard to AUCGIR,τ,SS (the primary endpoint of this study) and GIRmax,IDeg,SS. Estimated mean age group ratios (elderly/younger adult) for AUCGIR,τ,SS and GIRmax,IDeg,SS and corresponding two-sided 95 % CIs were 0.78 (95 % CI 0.47–1.31) and 0.80 (95 % CI 0.54–1.17), respectively. Duration of action was beyond the clamp duration of 26 h in all subjects. ConclusionsThe exposure of IDeg at steady state during once-daily dosing was similar in younger adult and elderly subjects. The glucose-lowering effect of IDeg was numerically lower in elderly subjects compared with younger adults, but no significant differences were observed between age groups. The ultra-long pharmacokinetic and pharmacodynamic properties of IDeg observed in younger adults were preserved in elderly subjects with type 1 diabetes.Clinical trials.gov number: NCT00964418

Development of a liquid chromatography-mass spectrometry method for the determination of the neurotoxic quinolinic acid in human serum.

BACKGROUND Quinolinic acid (QA) is thought to be one of the most important metabolites of the kynurenine pathway with the highest biological activity in apoptotic responses and neurodegenerative diseases. The determination of QA might be of clinical relevance in different patient groups, but currently, only a few laborious methods with high levels of sample volume consumption are available. METHODS We developed and validated a simple liquid chromatography-tandem mass spectrometric (LC-tandem MS) method for the determination of QA in human serum with low sample volume requirements. RESULTS The presented method provides high sample throughput with 25 μL aliquots and works in the positive electrospray ionization (ESI) mode. A commercially available QA-d3 was used as internal standard. Specific transitions for QA and QA-d3 were m/z 280→m/z 78 and m/z 283→m/z 81, respectively. The intra- and inter-assay coefficients of variation (CVs) were all below 10%. Applying this method, in 50 healthy humans a mean serum concentration of QA of 350±167 nmol/L (mean±SD) was determined. CONCLUSION The described method is suitable for large clinical trials, which is of potential clinical importance to elucidate the function of QA and its relationship to different disease patterns and may be applicable for clinical laboratory routine.

Efficacy, usability and sequence of operations of a workflow‐integrated algorithm for basal–bolus insulin therapy in hospitalized type 2 diabetes patients

To evaluate glycaemic control and usability of a workflow‐integrated algorithm for basal–bolus insulin therapy in a proof‐of‐concept study to develop a decision support system in hospitalized patients with type 2 diabetes.

Effects of Vitamin D Supplementation on Bone Turnover Markers: A Randomized Controlled Trial

Bone turnover markers (BTMs) are used to evaluate bone health together with bone mineral density and fracture assessment. Vitamin D supplementation is widely used to prevent and treat musculoskeletal diseases but existing data on vitamin D effects on markers of bone resorption and formation are inconsistent. We therefore examined the effects of vitamin D supplementation on bone-specific alkaline phosphatase (bALP), osteocalcin (OC), C-terminal telopeptide (CTX), and procollagen type 1 N-terminal propeptide (P1NP). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial, a single-center, double-blind, randomized, placebo-controlled trial (RCT) performed at the Medical University of Graz, Austria (2011–2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D (25[OH]D) levels <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for eight weeks. One hundred ninety-seven participants (60.2 ± 11.1 years; 47% women) were included in this analysis. Vitamin D had no significant effect on bALP (mean treatment effect (MTE) 0.013, 95% CI −0.029 to 0.056 µg/L; p = 0.533), CTX (MTE 0.024, 95% CI −0.163 to 0.210 ng/mL, p = 0.802), OC (MTE 0.020, 95% CI −0.062 to 0.103 ng/mL, p = 0.626), or P1NP (MTE −0.021, 95% CI −0.099 to 0.057 ng/mL, p = 0.597). Analyzing patients with 25(OH)D levels <50 nmol/L separately (n = 74) left results largely unchanged. In hypertensive patients with low 25(OH)D levels, we observed no significant effect of vitamin D supplementation for eight weeks on BTMs.

Distribution of CD4pos -, CD8pos – and Regulatory T Cells in the Upper and Lower Gastrointestinal Tract in Healthy Young Subjects

The gastrointestinal immune system is involved in the development of several autoimmune-mediated diseases, including inflammatory bowel disease, multiple sclerosis, and type 1 diabetes mellitus. Alterations in T-cell populations, especially regulatory T cells (Tregs), are often evident in patients suffering from these diseases. To be able to detect changes in T-cell populations in diseased tissue, it is crucial to investigate T-cell populations in healthy individuals, and to characterize their variation among different regions of the gastrointestinal (GI) tract. While limited data exist, quantitative data on biopsies systematically drawn from various regions of the GI tract are lacking, particularly in healthy young humans. In this report, we present the first systematic assessment of how T cells—including Tregs—are distributed in the gastrointestinal mucosa throughout the GI tract of healthy young humans by means of multi-parameter FACS analysis. Gastroduodenoscopy and colonoscopy were performed on 16 healthy volunteers aged between 18 and 32. Biopsies were drawn from seven GI regions, and were used to determine the frequencies of CD8+-, CD4+- and Tregs in the gastrointestinal mucosa by means of multi-parameter FACS analysis. Our data show that there is significant variation in the baseline T-cell landscape along the healthy human gastrointestinal tract, and that mucosal T-cell analyses from a single region should not be taken as representative of the entire gastrointestinal tract. We show that certain T-cell subsets in the gastrointestinal mucosa vary significantly among regions; most notably, that Tregs are enriched in the appendiceal orifice region and the ascending colon, and that CD8pos T cells are enriched in the gastric mucosa.